Exploitation of synthetic lethal relationship is a trustworthy therapeutic strategy to target genetic differences between tumor and normal cells which eventually provide large therapeutic window for the treatment of cancer. Poly (ADP-ribose) polymerase-1(PARP-1, 113 kDa) is a prototype member of the 17 member PARP protein superfamily. PARP-1 is a nuclear protein whose zinc finger DNA binding domain localizes PARP-1 to the site of DNA damage. This NAD dependent enzyme catalyzes poly (ADP-ribosylation) of proteins, involved in the detection and repair of DNA damage. It plays a frontal role in the decision of a cell to live or to die in a stress situation [Senthil kumar B., Rajmohan, et al., Mol. Cell. Biol. 2009, 29(15), 4116-4129]. The primary structure of the enzyme is highly conserved in eukaryotes with human enzyme having 92% homology with mouse enzyme at the level of amino acid sequence and a 50 amino acid block showing 100% homology between vertebrates [Virag Laszlo and Szabo Csaba, Pharmacol. Reviews 2002, 54(3), 375-429]. Studies on the molecular mechanism of PARP-1 suggests that, it is involved in various DNA related functions including gene amplifications, cell division, differentiation, apoptosis, DNA base excision repair and also effects on telomere length and chromosome stability [d'Add di Fagogna et al., Nature Gen. 1999, 23(10), 76-80].
It has been reported that PARP-1 modulates DNA repair and other processes and can produce long chains of poly (ADP-ribose) within the cell nucleus which is central to its activity [Althaus, F. R.; Richter, C. Mol. Biol., Biochem. Biophys. 1987, 37, 1-237]. Different studies on knock out mouse models, report that the deletion of PARP-1 impairs DNA repair but is not embryonically lethal. Double knock out PARP-1 and PARP-2 mice die during early embryogenesis, which shows that PARP-2 as the closest homolog of PARP-1 (62% identical in its catalytic domain to PARP-1) & plays a major role in the DNA repair during the absence of PARP-1 enzyme [Ratnam Kapil and Law Jenifer A. Clin. Cancer Res. 2007, 17(5), 1383-1388]. A group of scientists from Newcastle University and University of Konstanz, in British Journal of Cancer 2009, 101(2), 256-26, claims to be the first to directly compare PARP-1 polymorphisms, cellular levels of PARP-1 protein and PARP activity in a systematic way and reveals that PARP activity depends on other factors beside the level of protein and the active site SNP.
In a recent review from Free Radical Biology & Medicine 2009, 47, 13-26 suggests that PARP inhibitors could be used not only as chemo/radiotherapy sensitizers, but also as single agents to selectively kill cancers which are due to defect in DNA repair, specifically cancers with mutations in the breast cancer-associated gene (BRCA1 and BRCA2). PARP becomes activated in response to oxidative DNA damage and depletes cellular energy pools, thus leading to cellular dysfunction in various tissues. The activation of PARP may also induce various cell death processes and promotes an inflammatory response associated with multiple organ failure.
Recently some of the investigators have demonstrated in Biochem. Pharmacol. 2009, 77, 1348-1357 that PARP inhibitors combined with DNA-damage inducing cytostatic agents like taxol can lead to effective tumor therapy through activation of PI-3-kinase-Akt pathway.
The American Society of Clinical Oncology held its Annual Meeting in Orlando, Fla. (May 29-Jun. 2, 2009) and as reported in Eur. J. Cancer 2009, 45, 1897-1901 that two drugs Olaparib and BSI-201 from a new class of targeted agents called poly (ADP-ribose) polymerase (PARP) inhibitors have demonstrated significant activity against hard-to treat breast cancers, according to findings from two separate phase II trials.
Several small molecules that specifically target PARP-1 enzyme as an inhibitor are being investigated and among them BSI 201 (BiPar) is in Phase III clinical trial and AG 14699 (Cancer Res. UK), AZD 2281 (KuDOS), ABT 888 (Abbott) are in Phase II clinical trial, with promising initial results. However, special attention must be paid to the possibility that enhanced therapeutic efficacy might be accompanied by increased off-target effects because of effect on DNA-repair mechanism in normal tissues.
Recent findings have thrust poly(ADP-ribose) polymerases (PARPs) into the limelight as potential chemotherapeutic targets as described in Nature Reviews Cancer 4 Mar. 2010, 1-9. Crystal Structure of the Catalytic Domain of Human PARP2 in Complex with PARP Inhibitor ABT-888 reported by [Herwig Schuler et al., Pharmacol. Biochemistry 2010, 49, 1056-1058]
Novel compounds which are selective PARP-1 inhibitors, their preparation and their use in medicine have also been reported in WO 2002036576, WO 2006039545, WO 2007062413, WO 2004080976, WO 2009093032, WO 2008047082, WO 2001042219, WO 2005066163, WO 2006106326, WO 2008146035, WO 2006021801, US 20090192156, WO 2012019427, WO 2012071684, WO 2012019426, WO 2012072033, which are incorporated as references in their entirety.
Synthesis of pthalazinone derivatives of the following general formula and having the potential to inhibit PARP for the treatment of cancer or for potentiating tumor cells for the treatment with ionizing radiation or chemotherapeutic agents has been disclosed in US 2009/0192156 A1 and WO 2009/093032 A1.

Synthesis of thiophene carboxamide class of compounds as the combination of CHK and PARP inhibitors for the treatment of cancer is disclosed in WO 2008146035 A1 and WO 2005066163 A2. Representative compounds have the following general formula,

Wherein X is selected from NH, S and O. Y is selected from CH or N.
Crystalline form and improved method for the synthesis of particular pthalazinone derivatives and use of the crystalline form as PARP-1 inhibitor has been reported in WO 2008047082. Representative compounds have the following structure:

Synthesis of 4-heteroarylmethyl substituted pthalazinone derivatives has been disclosed in WO 2006021801 A1 and WO 2004080976 A1 for use in treating cancer or other diseases ameliorated by the inhibition of PARP.
wherein, A and B together represent an optionally substituted, fused aromatic ring; X can be NRX or CRXRY; If X═NRX then n is 1 or 2 and if X═CRXRY then n is 1; RX is selected from the group consisting of H, optionally substituted C1-20 alkyl, C1-20 aryl, C(3-20) heterocyclyl, thioamido, ester, acyl, and sulfonyl groups; RY is selected from H, hydroxyl, amino; RX and RY may together form a spiro C3-7 cycloalkyl or heterocyclyl group; RC1 and RC2 are independently selected from the group consisting of H and C1-4 alkyl; R1 is selected from H and halo; And Het is selected from
where Y1 is selected from CH and N, Y2 is selected from CH and N, Y3 is selected from CH, CF and N, where one or two of Y1, Y2, and Y3 can be N; and
wherein Q is O or S.
Optimization of Phenyl-Substituted Benzimidazole Carboxamide Poly(ADP-Ribose) 5-Benzamidoisoquinolin-1-ones and 5-(ω-Carboxyalkyl)isoquinolin-1-ones as Isoform-Selective Inhibitors of Poly(ADP-ribose) Polymerase 2 (PARP-2) has been described in J. Med. Chem. 2011, 54, 2049-2059 by Peter T. Sunderland et. al.
Tumor Growth Inhibition by Olaparib in BRCA2 Germline-Mutated Patient-Derived Ovarian Cancer Tissue Xenografts has been recently published in Clin Cancer Res 2011, 17, 783-791.
Simultaneous determination of ABT-888, a poly (ADP-ribose) polymerase inhibitor, and its metabolite in human plasma by liquid chromatography/tandem mass spectrometry has been described in Journal of Chromatography B, 2011, 878, 333-339.
“Evolution of Poly(ADP-ribose)Polymerase-1 (PARP-1) inhibitors, From Concept to Clinic” a review article by Dana V. Ferraris has been published in J. Med. Chem. 2010, 53, 4561-4584, which describes in details of the efforts by different pharmaceutical industries and academic institutions in the development of the PARP 1 inhibitors.
“Development of substituted 6-[4-fluoro-3-(piperazin-1-ylcarbonyl)benzyl]-4,5-dimethylpyridazin-3-(2H)-ones as potent poly(ADP-ribose)polymerase-1 (PARP-1) inhibitors active in BRCA deficient cells” article has been published by Federica Ferrigno et al. in Bioorg. Med. Chem. Lett. 2010, 20, 1100-1105.
‘Polymerase Inhibitors: Identification of (S)-2-(2-Fluoro-4-(pyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide (A-966492), a highly Potent and Efficacious Inhibitor’ has been described in J. Med. Chem., 2010, 53, 3142-3153.

Design, synthesis of Quinoline-8-carboxamides, a new class of Poly (adenosine-diphosphate-ribose) polymerase-1 (PARP-1) Inhibitor has been described in J. Med. Chem. 2009, 52, 868-877. Synthesis of 2-[(R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide as a Poly (ADP-ribose) Polymerase (PARP) Inhibitor has been disclosed in J. Med. Chem. 2009, 52, 514-523.

Synthesis of aminoethyl pyrrolo dihydroisoquinolinones as novel poly (ADP-ribose) polymerase-1 inhibitors has been described in Bioorg. Med. Chem. Lett. 2009, 19, 4042-4045. Representative compounds have the following general formula.

Synthesis of isoquinolinone-based tetracycles as poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors has been described in Bioorg. Med. Chem. Lett. 2009, 19, 7537-7541. Representative compounds have the following general formula.

Identification of substituted pyrazolo[1,5-a]quinazolin-5(4H)-one as potent poly(ADP-ribose)polymerase-1 (PARP-1) inhibitors has been described in Bioorg. Med. Chem. Lett. 2009, 19, 4196-4200. Representative compounds have the following general formula

Synthesis of novel tricyclic quinoxalinone as the inhibitors of poly (ADP-ribose) polymerase-1 (PARP-1) has been stated in Bioorg. Med. Chem. Lett. 2009, 19, 4050-4054. Representative compounds have the following general formula.

Identification of ring-fused pyrazolo pyridin-2-ones as novel poly (ADP-ribose) polymerase-1 inhibitors has been published in Bioorg. Med. Chem. Lett. 2008, 18, 5126-5129. This describes compounds of the following general formula.

Discovery of Orally Active and Brain-Penetrable Quinoxalinone Inhibitors of Poly (ADP-ribose) polymerase has been disclosed in J. Med. Chem. 2004, 47, 4151-4154 and describes compounds of the following general formula.

Discovery of potent Poly(ADP-ribose) Polymerase-1 Inhibitors from the modification of Indeno[1,2-c]isoquinolinone and the described compounds of the following general formula I has been reported in J. Med. Chem. 2005, 48, 5100-5103.

WO 2012 019426 discloses PARP inhibitors of the following general formula (I)
wherein: A and B are connected together to the carbon atoms to form a cycloalkyl group, heterocyclic group, aryl or heteroaryl group, Each of the ring atoms D or E is independently selected from C or N atoms; when n is 1, D and E are connected to one another to accomplish 6˜10-membered ring X; This specification is incorporated as reference in its entirety.
WO 2012 072033 discloses compounds of formula I or II, their isomers, salts, solvates, chemically protected form, and prodrugs:
wherein the substituents are as defined in the specification which is incorporated in entirety as reference.
New Gen Therapeutics, Inc has published a patent WO 2012166983 and disclosed tricyclic inhibitors of poly(ADP-ribose)polymerase.
Substituted 4-(4-fluoro-3-(piperazine-1-carbonyl)benzyl)phthalazin-1(2H)-one derivatives as Poly (ADP-ribose) polymerase-1 inhibitors has been published in WO 2012014221 by Cadila Healthcare Ltd. and discloses the following general structure

Shanghai Institute of Materia Medica, Chinese Academy of Science disclosed 2-Arylbenzofuran-7-formamide compounds preparation method and use thereof in patent WO 2013117120 and mentions the following formula:

Merck disclosed tetrahydro-quinazolinone derivatives as tankyrase and PARP inhibitors in patent WO 2013/117288 and mentions the following general structure

Novel compounds having PARP inhibitory activity has been disclosed by Santen Pharmaceutical Co. Ltd. in a patent WO 2013/008872 and the following formula has been disclosed.

Fused tetra or penta-cyclic pyridophthalazinones as PARP inhibitors have been reported by Belgena, Ltd. in a patent WO 2013097226.
AstraZeneca AB has published a patent U.S. Pat. No. 8,475,842 for immediate release pharmaceutical formation of 4-[3-4(cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2H-phthalazin-1-one.
BioMarin recently published a patent US 2013/0053365 and disclosed the formula (M)

Though several compounds have been reported in the literature as PARP-I inhibitors, very few have actually shown actual clinical benefits and none have been approved so far. Looking at the large unmet medical needs, there appears a need for developing further compounds which have better safety and efficacy profile. We herein disclose a new series of compounds which shows potential as PARP-I inhibitors.